What causes elevated lactic acid levels in patients, particularly those with a history of diabetes, kidney disease, or liver disease, and taking medications such as metformin?

What Causes High Lactic Acid

Elevated lactic acid results from either tissue hypoxia causing overproduction (Type A) or metabolic disturbances causing underutilization (Type B), with the most critical causes being circulatory shock, severe infections, metformin accumulation in renal/liver impairment, and mitochondrial dysfunction.

Type A Lactic Acidosis: Tissue Hypoxia and Overproduction

Type A occurs when tissues must regenerate ATP without oxygen, producing lactate at rates that overwhelm clearance mechanisms 1.

Primary Circulatory Causes

• Shock states (septic, cardiogenic, hypovolemic) cause inadequate tissue perfusion and are the most common cause of Type A lactic acidosis 2
• Cardiac failure leads to inadequate tissue perfusion 2
• Severe infections, particularly in patients with diabetes, trigger anaerobic metabolism 2
• Mesenteric ischemia presents with the combination of lactic acidosis and elevated urea (88% of patients show metabolic acidosis with elevated lactate) 2

Other Type A Mechanisms

• Rhabdomyolysis causes damaged muscle tissue to undergo anaerobic metabolism, producing lactate 2
• Cyanide poisoning blocks cellular oxygen utilization despite adequate delivery 1
• Certain malignancies increase lactate production through altered metabolism 1

Type B Lactic Acidosis: Impaired Clearance and Metabolic Dysfunction

Type B occurs without tissue hypoxia, involving either impaired lactate clearance or metabolic disturbances that increase production 1.

Medication-Induced Causes

Metformin is the most clinically significant drug cause, with incidence of 2-9 per 100,000 patients/year, but risk increases dramatically with renal impairment 2, 3:

• Metformin decreases liver uptake of lactate, increasing blood levels and risk of acidosis 3
• Renal impairment (eGFR <30 mL/min/1.73 m²) causes metformin accumulation since the drug is substantially excreted by kidneys 3
• Liver disease impairs lactate clearance since the liver is the major site of lactate removal through gluconeogenesis 2, 4
• Acute illness (sepsis, dehydration, surgery) creates dynamic risk even with normal baseline renal function 5, 3

Nucleoside reverse transcriptase inhibitors (NRTIs), particularly stavudine and didanosine, cause mitochondrial toxicity with incidence of 1.3 cases per 1,000 person-years of exposure 2:

• Risk factors include obesity, female sex, prolonged use (>6 months), and pregnancy 2
• Mechanism involves inhibition of DNA polymerase γ, disrupting mitochondrial DNA synthesis 2

Organ Dysfunction

• Liver disease impairs lactate clearance through reduced gluconeogenesis and oxidation capacity 2, 1
• Renal impairment reduces lactate clearance (kidneys contribute to removal) and causes metformin accumulation 2, 3
• Chronic kidney disease causes hyperlactatemia in 30-65% of adults 2

Metabolic and Nutritional Causes

• Thiamine deficiency causes pyruvate dehydrogenase dysfunction, impairing lactate oxidation 2, 1
• D-lactic acidosis occurs in patients with short bowel syndrome and preserved colon from bacterial fermentation 2
• Severe hypophosphatemia (<0.32 mmol/L) triggers lactic acidosis, particularly in refeeding syndrome or during prolonged dialysis 2

Other Metabolic Causes

• Severe hypothyroidism can cause hyperlactatemia 2
• Inborn errors of metabolism (methylmalonic acidemia, propionic acidemia, maple syrup urine disease) 2

High-Risk Clinical Scenarios

Metformin Users at Highest Risk

The FDA contraindications and warnings identify specific high-risk situations 3:

• eGFR <30 mL/min/1.73 m² (absolute contraindication) 3
• Age ≥65 years (higher likelihood of hepatic, renal, or cardiac impairment) 3
• Acute kidney injury from any cause (sepsis, hypotension, contrast procedures) 5, 3
• Hospitalized patients with dynamic clinical conditions creating rapid risk factor development 5
• Iodinated contrast procedures in patients with eGFR 30-60 mL/min/1.73 m² or history of liver disease, alcoholism, or heart failure 3
• Surgery or NPO status (volume depletion, hypotension risk) 3
• Hypoxic states (acute CHF with hypoperfusion, MI, sepsis) 3
• Excessive alcohol intake (potentiates metformin's effect on lactate metabolism) 3

COVID-19 and Metformin

COVID-19 infection increases lactic acidosis risk in metformin users (adjusted hazard ratio 4.46), particularly with higher doses, worse kidney function, and greater disease severity 5, 2.

Diagnostic Thresholds

Laboratory criteria for lactic acidosis 2:

• Lactate >2 mmol/L: Elevated, criterion for sepsis
• Lactate >5 mmol/L: Abnormal, suggests metformin-associated lactic acidosis 3
• Lactate >10 mmol/L: Serious/life-threatening 2
• Arterial pH <7.3-7.35: Defines lactic acidosis 2
• Increased anion gap (>16 mEq/L): Characteristic finding 2

Critical Clinical Pitfalls

Do not ignore subtle early symptoms of metformin-associated lactic acidosis: nonspecific GI symptoms, dyspnea, generalized weakness, and myalgias often precede severe acidosis 2, 3.

Do not miss mesenteric ischemia when lactic acidosis combines with elevated urea and abdominal pain—this requires immediate CTA, as diagnostic delay is the dominant mortality factor (30-70%) 2.

Do not rely on normal blood pressure to exclude tissue hypoperfusion—hyperlactatemia without hypotension can indicate occult organ dysfunction requiring full evaluation 2.

Proper lactate measurement requires prechilled fluoride-oxalate tubes, transport on ice, processing within 4 hours, and collection without tourniquet or fist-clenching 2.